PMID: 11165106Feb 13, 2001Paper

In situ nasal absorption of midazolam in rats

International Journal of Pharmaceutics
J C OlivierW Couet

Abstract

Intranasal (i.n.) midazolam (MDZ) administrations may be used successfully for preoperative sedation, especially in young patients. However, clinicians have to use the commercial parenteral formulation, the low pH of which (3.3), necessary to solubilize MDZ (pK(a) 6.1), is probably responsible for the signs of local irritation frequently reported. As a starting point to design a formulation suitable for the nasal route, MDZ nasal absorption was investigated in rats. The effects of the MDZ solution concentration (10--100 microg/ml), osmolality (from less than 10 mOsm/kg up to 450 mOsm/kg) and pH (3.3--7.4) were studied using an in situ perfusion technique. MDZ was determined by reversed-phase HPLC in the circulating solution and results were expressed in clearance terms. MDZ absorption was independent of its concentration. The pH of the solutions was the key-parameter and only a pH above 4 allowed significant absorption. These results were consistent with a passive diffusion absorption of MDZ and partly followed the pH partition theory. In conclusion, satisfactory MDZ absorption should be expected with a formulation at a pH suitable for the nasal route in human (5.5--6.5).

References

Dec 1, 1988·Anesthesiology·N C WiltonU A Pandit
Nov 1, 1986·Anesthesiology·C Saint-MauriceG Olive
Sep 2, 1998·European Journal of Drug Metabolism and Pharmacokinetics·P OdouH Robert
Apr 18, 2000·International Journal of Pharmaceutics·N WashingtonD A Rawlins

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Citations

Apr 4, 2003·International Journal of Pharmaceutics·Christine DufesJean-Marc Muller
Jan 18, 2007·Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology·Eli O Meltzer
Jan 6, 2009·BMC Neuroscience·Henry R CostantinoSteven C Quay
Jul 28, 2012·Therapeutic Delivery·Catherine CampbellAnthony W Fox
Jun 30, 2005·Journal of Pharmaceutical Sciences·Alexis Kays LeonardHenry R Costantino

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